Featured
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Article
| Open Access
Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants
Cognitive variability with age has been examined in 21,051 recallable volunteers and has highlighted a potential role of microglia and glycogen metabolism in the individual differences in general cognitive ability.
- Md Shafiqur Rahman
- , Emma Harrison
- & Patrick F. Chinnery
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Article |
APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease
The study on APOE4 homozygosity indicates a genetic variant of Alzheimer’s disease with early symptom onset and distinct biomarker progression, highlighting the need for specialized treatment approaches.
- Juan Fortea
- , Jordi Pegueroles
- & Víctor Montal
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Research Briefing |
Revealing clinical heterogeneity in a large brain bank cohort
Clinical disease trajectories that describe neuropsychiatric symptoms were identified using natural language processing for 3,042 brain donors diagnosed with various neurodegenerative disorders. Trajectories revealed distinct temporal patterns that result in the identification of new clinical subtypes, and a subset of misdiagnosed donors.
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Article
| Open Access
Identification of clinical disease trajectories in neurodegenerative disorders with natural language processing
Analyzing clinical records from a cohort of 3,042 donors in the Netherlands Brain Bank, natural language processing models unveil the symptomatology and potential misdiagnoses of a broad range of neurodegenerative disorders.
- Nienke J. Mekkes
- , Minke Groot
- & Inge R. Holtman
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Article
| Open Access
Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests
The performance of plasma %p-tau217 is clinically equivalent in classification of Aβ PET status and superior in classification of tau PET status compared to clinically used and FDA-approved CSF tests in cognitively impaired participants.
- Nicolas R. Barthélemy
- , Gemma Salvadó
- & Oskar Hansson
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Article
| Open Access
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
A small number of patients who received growth hormone preparations contaminated with seeds of the amyloid-beta protein developed Alzheimer’s disease many years after treatment.
- Gargi Banerjee
- , Simon F. Farmer
- & John Collinge
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Research Briefing |
Events in the brain during the evolution of Alzheimer’s disease
Alzheimer’s disease is a complex and chronic disease that evolves over decades. Proteomic analysis of cerebrospinal fluid from people with dominantly inherited forms of the disease reveals the temporal progression of pathological changes in Alzheimer’s disease and identifies extracellular matrix proteins as some of the earliest biomarkers of the disease.
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Research Briefing |
A fluid biomarker accurately detects tau aggregate pathology in Alzheimer’s disease
Cost-effective fluid biomarkers for tau aggregate pathology would improve the diagnostic and prognostic work-up of Alzheimer’s disease and facilitate the discovery of anti-tau therapies. We identified MTBR-tau243 as a specific marker for tau aggregate pathology that could be implemented in clinical practice and trials.
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Article
| Open Access
Clinical effects of Lewy body pathology in cognitively impaired individuals
Prospective and longitudinal analyses of patients with cognitive impairment reveal that in vivo detection of Lewy body pathology is independently associated with hallucinations, worse attention/executive, visuospatial and motor function and predicted future cognitive decline.
- Corinne Quadalti
- , Sebastian Palmqvist
- & Piero Parchi
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Article
| Open Access
CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
CSF MTBR-tau243 is more related to tau tangles and clinical cognitive impairment in Alzheimer’s disease than phospho-tau biomarkers, which are more related to amyloid plaques.
- Kanta Horie
- , Gemma Salvadó
- & Randall J. Bateman
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News & Views |
Clonal hematopoiesis, aging and Alzheimer’s disease
Unexpectedly, new data show that clonal hematopoiesis is associated with protection from Alzheimer’s disease; it is imperative that future studies unravel the complex tissue–disease contexts in which clonal hematopoiesis arises and contributes to aging-associated diseases.
- Pablo Sánchez Vela
- , Jennifer J. Trowbridge
- & Ross L. Levine
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Correspondence |
In global approaches to dementia research, do not forget care
- Fanny Monnet
- , Charlèss Dupont
- & Lara Pivodic
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Article
| Open Access
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
Evaluation of a tau-targeting antisense oligonucleotide in a phase 1 trial of patients with mild AD found it was well tolerated and resulted in a sustained reduction of tau protein levels.
- Catherine J. Mummery
- , Anne Börjesson-Hanson
- & Roger M. Lane
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Article
| Open Access
Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline
Abnormal amyloid and tau PET in cognitively unimpaired individuals is strongly associated with short-term cognitive decline and subsequent development of dementia.
- Rik Ossenkoppele
- , Alexa Pichet Binette
- & Oskar Hansson
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Article |
Temporal order of clinical and biomarker changes in familial frontotemporal dementia
Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs
- Adam M. Staffaroni
- , Melanie Quintana
- & Sónia Afonso
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Brief Communication
| Open Access
Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease
A comprehensive comparison of Alzheimer’s disease blood biomarkers in cognitively unimpaired individuals reveals that plasma p-tau231 and p-tau217 capture very early Aβ changes, showing promise as markers to enrich a preclinical population for Alzheimer’s disease clinical trials
- Marta Milà-Alomà
- , Nicholas J. Ashton
- & Kaj Blennow
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Article |
Microglial activation and tau propagate jointly across Braak stages
Microglial activation and tau accumulation propagate together in patients with Alzheimer’s disease, suggesting an interaction that determines disease progression.
- Tharick A. Pascoal
- , Andrea L. Benedet
- & Pedro Rosa-Neto
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News & Views |
Dominantly inherited Alzheimer’s disease: a compass for drug development
The first phase 3 trial of amyloid-β-targeting monoclonal antibodies in dominantly inherited Alzheimer’s disease failed to slow cognitive decline in patients. Could it still help to inform future study design and drug development in this setting?
- Gil D. Rabinovici
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Article |
A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
Results from the phase 2/3 clinical trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease reveal no beneficial effects on cognitive measures despite a significant reduction in amyloid plaques and other key biomarkers in those treated with gantenerumab.
- Stephen Salloway
- , Martin Farlow
- & Christopher H. van Dyck
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Article |
Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures
Plasma P-tau, in combination with clinical measures, predicts future Alzheimer’s disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists.
- Sebastian Palmqvist
- , Pontus Tideman
- & Oskar Hansson
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News & Views |
Another step forward in blood-based diagnostics for Alzheimer’s disease
Measurement of phosphorylated tau protein in blood plasma allows Alzheimer’s disease to be distinguished from other neurological diseases and may assist in disease detection during the prodromal stage.
- Randall J. Bateman
- , Nicolas R. Barthélemy
- & Kanta Horie
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Article |
Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia
Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
- Shorena Janelidze
- , Niklas Mattsson
- & Oskar Hansson
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Article |
Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration
Plasma pTau181 concentrations are elevated specifically in patients diagnosed with Alzheimer’s disease compared to those diagnosed with frontotemporal lobar degeneration or elderly controls, supporting its further development as a blood-based biomarker for AD.
- Elisabeth H. Thijssen
- , Renaud La Joie
- & Bradford C. Dickerson
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News & Views |
Imaging the glutamate synapse
A new positron emission tomography radiotracer enables imaging of the human glutamate receptor AMPA-R, a fundamental component of neurotransmission involved in neuropsychiatric disorders.
- John H. Krystal
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Brief Communication |
Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report
A unique case from the Colombian cohort of autosomal dominant Alzheimer’s disease is reported in which disease progression is substantially delayed despite unusually high amyloid plaque pathology, possibly related to a rare mutation in APOE3.
- Joseph F. Arboleda-Velasquez
- , Francisco Lopera
- & Yakeel T. Quiroz
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News & Views |
Genetic predisposition and modifiable risks for late-life dementia
Modifiable lifestyle risk factors are able to reduce dementia risk only in people with low genetic risk.
- Kenneth Rockwood
- , Lindsay M. K. Wallace
- & Daniel H. Davis
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Letter |
Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population
Genetic predispositions and lifestyle factors can interact to either confer protection against, or elevate risk for, development of clinical dementia in a prospective cohort of over 6,000 individuals from the population-based Rotterdam Study.
- Silvan Licher
- , Shahzad Ahmad
- & M. Kamran Ikram
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Article |
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia
Evolutionarily conserved gene modules mediate neurodegenerative dementia in a variety of mouse models and in postmortem brain tissue from patients.
- Vivek Swarup
- , Flora I. Hinz
- & Daniel H. Geschwind
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Article |
Neurogenetic contributions to amyloid beta and tau spreading in the human cortex
Cross-sectional and longitudinal PET imaging of amyloid beta and tau in the human brain is combined with gene expression profiles to define the interactions between Alzheimer’s disease-related pathology propagation and brain-region-specific vulnerability.
- Jorge Sepulcre
- , Michel J. Grothe
- & Keith A. Johnson
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Q&A |
Searching for Alzheimer’s disease therapies
The pathological hallmarks of Alzheimer’s disease (AD) include extracellular beta-amyloid plaques, neurofibrillary tangles, neuronal loss and tau deposits in brain. Therapies targeting these known hallmarks are yet to yield any meaningful benefit in clinical trials. We spoke to four researchers in the fields of AD research and therapy development to find out where they think the fields should head next.
- Hannah Stower
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News & Views |
A molecular mechanism governing memory precision
A key molecular mechanism has been identified that dictates whether memory will maintain or lose its details over time and that is relevant in post-traumatic stress disorder and dementia.
- Josue Haubrich
- & Karim Nader
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Brief Communication |
Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease
Using intracranial electrode recordings in two individuals with Alzheimer's disease, Lam et al. discover hippocampal seizure activity that could not be detected by traditional EEG monitoring.
- Alice D Lam
- , Gina Deck
- & Andrew J Cole
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Article |
The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity
ALS-associated mutations in TDP-43 enhance its localization to mitochondria, and the inhibition of mitochondrial targeting reduces neuronal toxicity and alleviates motor phenotypes induced by TDP-43 expression in mice in vivo.
- Wenzhang Wang
- , Luwen Wang
- & Xinglong Wang
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News & Views |
MicroRNA-124 modulates social behavior in frontotemporal dementia
Frontotemporal dementia (FTD) is a neurodegenerative disease that causes social dysfunction and other symptoms. A new study suggests that social dysfunction in FTD is due to decreased microRNA-124 expression and resulting changes in glutamate receptor composition in the prefrontal cortex.
- Andrew E Arrant
- & Erik D Roberson
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Article |
Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia
A new mouse model of frontotemporal dementia is described in which the mice show miR-124– and AMPA receptor–mediated social behavioral deficits.
- Eduardo Gascon
- , Kelleen Lynch
- & Fen-Biao Gao
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Article |
Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease
Tau cleavage and aggregation, key processes in many neurodegenerative diseases, can be reduced by blocking the activity of a protease called asparagine endopeptidase.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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Article |
GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease
In Alzheimer's disease, increased MAOB activity in reactive astrocytes leads to enhanced GABA release, and blockage of this pathway ameliorates memory dysfunction in mouse models.
- Seonmi Jo
- , Oleg Yarishkin
- & C Justin Lee
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News & Views |
Alzheimer's and prion diseases: PDK1 at the crossroads
TACE-mediated proteolysis is a key event interfering with both Alzheimer's and prion diseases. A new study shows that phosphoinositide-dependent kinase-1 (PDK1) is activated by cellular prion protein, which alters membrane-associated TACE levels, thereby influencing both Alzheimer's and prion pathologies (pages 1124–1131).
- Frédéric Checler
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Editorial |
Risk-takers wanted
Treating costly conditions such as Alzheimer's disease may soon collapse healthcare systems around the world, yet companies hesitate to invest in the long, large clinical trials required to discover disease-modifying therapies. New incentives are necessary to turn this tide.
Thromboembolic events and vascular dementia in patients with atrial fibrillation and low apparent stroke risk